Agonist-induced platelet activation results in platelet-endothelium and platelet-platelet interactions that lead to platelet aggregation, a process responsible for thrombus or hemostatic plug formation. Although the process plays an important role in repairing damaged vessel walls or wound healing, aberrant platelet aggregation is pathophysiological for arterial thrombosis.
Thrombosis is one of the main causes of death in the world and is involved in various disease conditions, such as cardiac infarction, unstable angina pectoris, stable angina pectoris, transitory ischemic attacks (TIA), stroke, peripheral arterial occlusion diseases, re-occlusions and restenosis after angioplasty or aortocoronary bypass, deep vein thromboses and arteriosclerosis.
A number of converging pathways lead to platelet aggregation, the final common event in which is a cross linking of platelets resulting from the binding of fibrinogen to the glycoprotein IIb/IIIa (GPIIb/IIIa) membrane binding site. The high anti-platelet aggregation efficacy of antibodies or antagonists for GPIIb/IIIa interferes with the binding of fibrinogen and also results in the adverse bleeding events observed with this class of agent. Thrombin can produce platelet aggregation largely independently of other pathways but substantial quantities of thrombin are unlikely to be present without prior activation of platelets by other mechanisms.
ADP (adenosine 5′-diphosphate) acts as a key mediator for thrombosis. A pivotal role for ADP is supported by the fact that other agents, such as adrenaline and 5-hydroxytryptamine (5HT, serotonin) will only produce aggregation in the presence of ADP. The limited anti-thrombotic activity of aspirin may reflect the fact that it blocks only one source of ADP released in a thromboxane-dependent manner following platelet adhesion. Aspirin has no effect on aggregation produced by other sources of ADP, such as damaged cells or ADP released under conditions of turbulent blood flow. ADP-induced platelet aggregation is induced by the purinoceptor P2T subtype receptor located on the platelet membrane.
Further, ADP released from aggregated platelet dense granules induces secondary aggregation via the feedback process that amplifies and propagates platelet activation induced by other agonists, such as collagen, thromboxin, 5HT, and serotonin. The inhibition of platelet aggregation induced by ADP is one of several antiplatelet drug mechanisms used for reducing the risk of clinical arterial and venous thrombotic events.
Current evidence suggests that there are three types of ADP receptor on platelet surfaces, classified as P2X1, P2Y1, and P2Y12 (also referred to as P2T, P2TAC, P2YADP, or P2cyc) receptors.
The P2Y1 receptor is linked to activation of phosphalipase C via the Gq protein and elevated cytosolic calcium and calcium influx via formation of IP3 and release of Ca++ from intracellular stores. These are involved in shape changes and transient aggregation. The P2Y12 receptor has been characterized pharmacologically using selective antagonists as the receptor linked via Gi to inhibition of adenylate cyclase. Accordingly, the P2Y12 receptor mediates a fall in the cyclic AMP level in response to ADP that further mediates degranulation and sustained aggregation.
Therefore, an ADP P2Y12 receptor antagonist would provide a more efficacious anti-thrombotic agent than aspirin or currently available therapies but with less profound effects on bleeding than other antagonists of the fibrinogen receptor.
PCT Application WO97/35539 (see U.S. Pat. Nos. 6,107,300 and 6,448,261) describes the preparation of arylamino fused pyridines and pyrimidines as CRF antagonists. U.S. Pat. No. 4,076,711 describes triazolopyrimidine compounds for the topical treatment of psoriasis. U.S. Pat. No. 6,458,796 describes triazolopyrimidine compounds as inhibitors of cGMP metabolizing phosphodiesterases. PCT Application WO04/018473 describes azapurine derivatives as cyclin-dependent kinase inhibitors.
The article ν-Triazolo[4,5-d]pyrimidines (8-azapurines). Part 18. Three new reactions for synthesizing 8-azapurinethiones from 4-amino-5-cyano-1,2,3-triazoles (Adrien A., Lin C. J., Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1977), (2), 210-13) describes a 3,4-dihydro-7-(phenylamino)-3-(phenylmethyl)-5H-1,2,3-triazolo[4,5-d]pyrimidine-5-thione compound.
Each of the following references describes cyclohexyl substituted triazolopyrimidine compounds: Teran C., Santana L., Uriarte E., Vina D., De Clercq E., Purine Derivatives of 1,2-Disubstituted Cyclohexane Analogues of Nucleosides, Nucleosides, Nucleotides & Nucleic Acids, (2003), 22(5-8), 787-789; Biagi G., Giorgi I., Livi O., Pacchini F., Rum P., Scartoni V., Costa B., Mazzoni M., Giusti, L., erythro- and threo-2-Hydroxynonyl substituted 2-phenyladenines and 2-phenyl-8-azaadenines: ligands for A1 adenosine receptors and adenosine deaminase, Farmaco, (2002), 57(3), 221-233; Biagi G., Giorgi I., Livi O., Scartoni V., Lucacchini A., N(9)-substituted 2-phenyl-N(6)-benzyl-8-azaadenines: A1 adenosine receptor affinity. A comparison with the corresponding N(6)-substituted 2-phenyl-N(9)-benzyl-8-azaadenines, Farmaco, (1996), 51(6), 395-399; Biagi G., Giorgi I., Livi O., Scartoni V., Breschi C., Martini C., Scatizzi, R., N(6) or N(9) substituted 2-phenyl-8-azaadenines: affinity for A1 adenosine receptors. VII, Farmaco, (1995), 50(10), 659-67; Kotva R., Semonsky M., Vachek J., Jelinek V., Substances with antineoplastic activity. XLI. δ-(8-Aza-6-purinylthio)valeric acid and some of its 9-alkyl and 9-cycloalkyl derivatives, Collection of Czechoslovak Chemical Communications, (1970), 35(5), 1610-13; Koppel H. C., O'Brien D. E., Robins, R. K., Potential purine antagonists. XIX. Synthesis of some 9-alkyl(aryl)-2-amino-6-substituted purines and related v-triazolo[d]pyrimidines, Journal of the American Chemical Society, (1959), 81, 3046-51; Leese C. L., Timmis G. M., Potential antipurines. II. Synthesis of 6- and 9-substituted purines and 8-azapurines, Journal of the Chemical Society, Abstracts, (1958) 4107-10
Each of the following references describes cyclohexenyl substituted triazolopyrimidine compounds: Konkel M. J., Vince R., Palladium-Catalyzed Allylic Coupling of 1,2,3-Triazolo[4,5-d]pyrimidines (8-Azapurines), Journal of Organic Chemistry, (1996), 61(18), 6199-6204; and, Konkel M. J., Vince R., Synthesis and biological activity of cyclohexenyl nucleosides. cis-5-(9H-Purin-9-yl)-3-cyclohexenyl carbinols and their 8-azapurinyl analogs, Nucleosides & Nucleotides, (1995), 14(9 & 10), 2061-77.